Small cells, big hopes

After 40 years, the U continues to lead the charge against cancer and other disorders with lifesaving blood and marrow transplants

Packed into the hollows of your bones, pulsing through your arteries
and veins, are millions of immature cells that play a very big role in
keeping you alive.

Known as hematopoietic stem cells, or HSCs, these cells produce the
blood cells that carry oxygen, keep you from bleeding to death, and
defend you against incursions by bacteria, viruses, and other
adversaries. HSCs are also the stars of blood and marrow
transplantation (BMT), a lifesaving therapy that has given thousands of
children and adults a new source of blood cells.

Forty years ago, University of Minnesota pediatrician Robert Good,
M.D., Ph.D., made history when he performed the world’s first
successful BMT using bone marrow taken from a matched sibling donor,
saving the life of a baby boy with an inherited immune deficiency.

Since then, University researchers and clinicians have led the way
in applying BMT to a variety of disorders. In 1975 physicians here
performed the first successful BMT in a patient with lymphoma. Seven
years later, the University was the first to use BMT to treat an
inherited metabolic disease. In the 1980s researchers developed a
protocol to use a patient’s own marrow to treat chronic myelogenous
leukemia. And over the past decade and a half, University
physician-researchers have pioneered the use of umbilical cord blood as
a source of HSCs for transplant and improved the applicability and
success of BMT in both children and adults.

And that’s just the beginning, says Daniel Weisdorf, M.D., professor of medicine and director of the adult blood and marrow transplant program.

“We’re still one of the major centers in the world,” he says. “We
have a new generation of very able people in clinical and preclinical
research. They’re going to take the program to the next phase of
success in the next 10 years.”

The good news? Rosenberg had recently moved to the Twin Cities. Her
mom, who lives in Boston, had suggested she go to a clinic attached to
a major hospital; her boyfriend happened to have a parking pass for the
University of Minnesota Medical Center, Fairview. Seemingly by chance,
and certainly by good fortune, Rosenberg ended up at one of the world’s
premier BMT centers.

Six weeks after a diagnosis of myelodysplastic syndrome, Rosenberg
underwent chemotherapy and total body irradiation to destroy the
remnants of her own failing marrow. She then received an infusion of
HSCs from her older brother, Mike. That was followed by months of
uncertainty as the donated cells and her body struggled to get along.
But she made it through—thanks, she says, to the expertise she found at
the University.

“I was so lucky to be right where I was,” Rosenberg says.

BMT is conceptually simple: out with the bad HSCs, in with the good.
In practice, it’s a complex and uncertain process involving multiple
hurdles. Among the first is finding a suitable source of donor cells.
Next, doctors must figure out just the right mix of chemotherapy and
radiation to destroy the patient’s own HSCs and suppress the immune
system (to avoid rejection) while minimizing damage to other tissues.
After the transplant, the focus is on coaxing the body and new cells to
accept one another. Meanwhile, the body must endure the temporary
absence of an innate source of immune, clotting, and oxygen-carrying
cells. The process of devising and refining each of these steps has
required—and continues to require—enormous amounts of research.

Expanding the universe

One area in which University researchers are making exciting inroads
is finding, and fine-tuning the use of, novel sources of HSCs. In some
cases, certain of the patient’s own HSCs can be removed and reimplanted
after treatment. More often, HSCs come from the bone marrow or blood of
a donor whose cells are compatible with the recipient’s. Rosenberg was
one of the lucky ones: She had a sibling whose cells matched hers
closely enough to serve as a source of HSCs. But one out of four
patients needing a BMT can’t find adequately matched blood or marrow
from a donor.

In the 1990s University researchers played a key role in introducing
what has become an increasingly important source of HSCs—umbilical cord
blood. Recently, research led by John Wagner,
M.D., professor and director of pediatric hematology-oncology and blood
and marrow transplantation, showed that for some types of leukemia a
transplant of imperfectly matched cord blood works as well as, if not
better than, matched bone marrow.

“This study suggests that cord blood need not be considered a
second-line therapy any longer,” Wagner says. “The fact that cord blood
is banked and readily available with little notice is a great
advantage. Now, the timing of transplantation can be dictated by the
patient’s needs as opposed to the availability of matched bone marrow.”

The University of Minnesota also pioneered the use of blood from two
umbilical cords in the treatment of adult patients. The double
transplant not only provides the quantity of HSCs an adult needs but
also appears to boost the immune system—a bonus doctors had not
anticipated, Weisdorf says.

University innovations in the ways patients are prepared for
transplant are making BMT an option for more patients. Until recently,
individuals who had other illnesses, were elderly, or were weak from
cancer therapy were not considered candidates for BMT because of
concerns they could not withstand the required chemo- and radiation
therapy.

But recent research has led to a reduced-intensity protocol that
makes such transplants possible with less severe chemotherapy and
radiation therapy preparation. Last fall, Claudio Brunstein,
M.D., Ph.D., assistant professor of medicine, reported success using
reduced-intensity preparation for transplant with blood from two
partially matched umbilical cords to treat patients with leukemia or
lymphoma who otherwise might have been in-eligible for transplant. The
procedure, known as the “Minneapolis regimen,” will be tested in a
national multicenter trial beginning this summer.

“We are getting good engraftment and survival in people we would have turned down a few years ago,” Weisdorf says.

Researchers are also stretching the boundaries of BMT by using
natural killer (NK) cells to knock stubborn cases of leukemia into
remission so the patient can undergo transplant. NK cells cruise the
bloodstream killing viruses and cells that seem foreign to them.
Because cancerous cells are actually “self” cells gone bad, NK cells
don’t always recognize them as invaders.

“About 10 years ago I was thinking about these cells, and I realized
that NK cells from a partially matched donor might be able to do the
job on leukemic cells that a person’s own NK cells can’t,” recalls Jeffrey Miller, M.D., professor of medicine and associate director of the Masonic Cancer Center, University of Minnesota.

He began testing his hypothesis, with promising results. Eight years
ago, after extensive research, Miller and colleagues began clinical
trials using donor NK cells to prepare patients with acute myelogenous
leukemia for BMT.

“So far, 10 of the 32 patients receiving NK therapy have gone into
remission,” Miller says. Buoyed by the success, researchers are now
developing protocols for mobilizing donated NK cells against other
cancers, including non-Hodgkin’s lymphoma and breast and ovarian
cancer. They also have completed the first clinical trial using NK
cells from cord blood, are looking at ways to combine NK treatment with
BMT in a single procedure, and are working to increase the sensitivity
of cancers to NK cells.

“Our goal is to take what we learn in patients back to the research
laboratory to test new ideas that optimally exploit NK cells as cancer
therapy,” Miller says.

Safer transplants

A major complication of BMT is graft-versus-host disease (GVHD), in
which donor cells attack the recipient’s tissue. Occurring in about
two-thirds of BMTs, GVHD is responsible for one-third of deaths after
transplant.

In hopes of reducing GVHD, Bruce Blazar,
M.D., professor and section chief of pediatric blood and marrow
transplantation, has turned his attention to regulatory T cells, or
T-regs. Present in the blood in minute quantities, T cells act as a
natural brake on immune reactions.

Researchers led by Brunstein recently began a clinical trial to find
out whether infusing T-regs with BMT diminishes GVHD. So far, the
results are promising.

“If [the use of T-regs] reduces the prevalence of GVHD and doesn’t
blunt the transplant effect, it would make transplant substantially
safer,” Weisdorf says. “This is the first trial actually testing how to
do this in people. We’re leading the pack because of work in Bruce
Blazar’s lab.”

Blazar hopes to improve BMT in other ways as well. “We would like to
find new approaches to reduce … injury to critical organs, such as
the thymus and lung, and reduce relapse rates after BMT,” he says. “In
addition, we plan to examine new approaches to preventing or repairing
tissue injury using protein-, gene-, or cell-based therapies.”

Meanwhile, Jakub Tolar,
M.D., Ph.D., assistant professor of pediatrics, is studying ways to use
selected HSCs to boost recovery from the chemotherapy and radiation
patients must undergo to prepare for BMT.

Beyond cancer

Cancers are the conditions most commonly treated with BMT. But
physicians also use BMT to treat patients with genetic disorders
characterized by the inability to make certain proteins. Known as
inherited metabolic and storage diseases, these rare ailments cause
bodily functions to deteriorate as toxic substances build up in the
absence of the enzymes that Break them down. Depending on the enzyme
involved, these diseases can lead to lethal dysfunction of various
organs, including the brain.

Researchers discovered in the 1980s that, in some cases,
transplanted HSCs can supply the missing enzyme. Today University
physicians perform nearly two transplants a month for a variety of
metabolic and storage diseases, including osteopetrosis, which causes
debilitating thickening of the bones; inherited leukodystrophies, which
damage the brain; and Hurler syndrome, which affects a number of organs.

The availability of cord blood is a boon to this type of treatment
because these diseases are often rapidly progressive—tragic
deterioration can occur in the time it takes to find and obtain cells
from a suitable marrow donor.

“We’ve made a lot of recent advances in how we’re doing transplants,
so the outcomes have improved,” says Paul Orchard, M.D., associate
professor of pediatrics and medical director of the inherited metabolic
and storage disease bone marrow transplantation program.

The University’s BMT program made national news last fall when
Wagner treated Nate Liao, a toddler from New Jersey, with stem cells to
correct a life-threatening skin disease called recessive dystrophic
epidermolysis bullosa (EB). EB is a genetic disorder in which the
protein that anchors skin and lining of the gastrointestinal tract to
the body is missing, so the tissues come off with minimal trauma—just
coughing or walking, for example. Tolar, Blazar, and Wagner had
previously demonstrated in animal studies that BMT might be able to
help correct the disorder. In just one year, Wagner and colleagues
translated this novel approach into a treatment for people with EB.

“This is just one more example of how basic investigators and
clinicians can work together to develop life-saving new therapies,”
says Wagner, who holds the Variety Club Chair in Molecular and Cellular
Therapeutics, the Children’s Cancer Research Fund Hageboeck Chair in
Pediatric Oncology, and the McKnight Presidential Chair in Hematology
and Oncology. “While not all such treatments will work in humans, stem
cell research brings hope to hundreds of thousands of children and
adults with life-threatening, debilitating diseases. We are on the
verge of a medical revolution.”